5-Aminomethyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid derivatives

ABSTRACT

2,3-Dihydro-2-oxo-1H-imidazole-4-carboxylic acid derivatives having a (substituted amino)methyl substituent at the 5-position, are useful as cardiotonics, antihypertensives and antithrombotic agents. The compounds are obtained by the reaction of an appropriate amine with a 5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid ester or amide.

The present invention relates to imidazole-4-carboxylic acid derivativeshaving an aminomethyl substituent at the 5-position. More particularly,it relates to compounds having the following general formula: ##STR1##wherein R is hydrogen, lower alkyl of 1-4 C, lower alkanoyl of 2-4 C, orbenzoyl; R¹ is hydroxy, lower alkoxy of 1-4 C, amino, (loweralkyl)amino, (lower alkyl)₂ amino or --NHR₅ wherein R₅ is phenyl,methylphenyl, dimethylphenyl or methoxyphenyl; R² is hydrogen or loweralkyl of 1-4 C; and --NR³ R⁴ is (lower alkyl)₂ amino, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, ##STR2## wherein R⁶ is lower alkyl of 1-4C, phenyl, halophenyl, methylphenyl, methoxyphenyl ortrifluoromethylphenyl; and pyridinium chloride. The present inventionfurther encompasses the pharmaceutically acceptable acid addition saltsand the lower alkyl quaternary ammonium salts of the aforesaid compoundswhich are not already quaternized.

The lower alkyl groups referred to above contain 1 to 4 carbon atoms.Examples of such lower alkyl groups are methyl, ethyl, propyl, isopropyland butyl. The lower alkanoyl groups referred to above contain 2 to 4carbon atoms and can be exemplified by acetyl, propionyl and butyryl.Examples of lower alkoxy are methoxy, ethoxy and propoxy. Examples ofthe halophenyl groups referred to above include fluorophenyl,chlorophenyl and bromophenyl. When --NR³ R⁴ is pyridinium chloride, thegroup consists of pyridine with a free valence on the nitrogen forattachment of the group to the remainder of the molecule. The pyridinenitrogen is thus quatenary so that the group must also contain an anion,preferably chloride.

Illustrative of the pharmaceutically acceptable acid addition salts ofthe compounds of the present invention are salts with inorganic acidssuch as, for example, hydrochloric, hydrobromic, sulfuric, phosphoricand like acids; with organic carboxylic acids such as, for example,acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic anddihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic,4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic,2-phenoxybenzoic, 2-acetoxybenzoic, mandelic and like acids; and withorganic sulfonic acids such as methanesulfonic acid andp-toluenesulfonic acid. Illustrative of quaternary ammonium salts arethose formed with lower alkyl halides such as methyl bromide, methyliodide, ethyl bromide and ethyl iodide.

Where R is hydrogen in the compounds of the present invention, severaltautomeric forms of the compounds are possible as follows: ##STR3##wherein the various groups are as defined earlier. These tautomers areacidic and can react with strong bases to form pharmaceuticallyacceptable salts of the following formulas: ##STR4## wherein the variousgroups are defined as above and M is a pharmaceutically acceptablealkali metal such as sodium or potassium. Throughout this disclosure,the term 2-oxo-1H-imidazole shall be taken to mean any of the tautomersor the tautomer salts as set forth above.

As examples of compounds of the present invention are the following:

Ethyl5-[[4-(4-chlorophenyl)-1-piperazinyl]methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate.

N,N-diethyl-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxamide.

Methyl5-[[4-(4-fluorophenyl)-1-piperazinyl]methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate.

5-[[4-(3-Bromophenyl)-1-piperazinyl]methyl]-2,3-dihydro-N-phenyl-2-oxo-1H-imidazole-4-carboxamide.

5-[[4-(2-Methylphenyl)-1-piperazinyl]methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxamide.

Ethyl2,3-dihydro-5-[(4-ethyl-1-piperazinyl)methyl]-2-oxo-1H-imidazole-4-carboxylate.

Ethyl2,3-dihydro-5-[1-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-oxo-1H-imidazole-4-carboxylate.

Ethyl2,3-dihydro-5-[(dipropylamino)methyl]-2-oxo-1H-imidazole-4-carboxylate.

2,3-Dihydro-5-(methoxycarbonyl)-N,N,N-triethyl-2-oxo-1H-imidazole-4-methanaminiumbromide.

1-[[2,3-Dihydro-5-(ethoxycarbonyl)-2-oxo-1H-imidazol-4-yl]methyl]pyridiniumchloride.

Ethyl2,3-dipropionyl-2,3-dihydro-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylate.

Ethyl1,3-dibenzoyl-2,3-dihydro-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylate.

Ethyl2,3-Dihydro-1,3-diethyl-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylate.

To obtain the compounds of the present invention, a 1,3-diacetylimidazolone such as a compound of the formula: ##STR5## wherein X ishydrogen is brominated to give the corresponding compound wherein X isBr. The reaction is carried out using N-bromosuccinimide in the presenceof a free radical initiator such as benzoyl peroxide in an appropriatesolvent such as carbon tetrachloride. The specific diacetyl startingmaterials are obtained from the corresponding 1,3-unsubstitutedimidazolone by acetylation with acetyl chloride or acetic anhydride.When R¹ is alkoxy, the starting ester is obtained by the proceduredescribed by Duschinsky and Dolan, J. Am. Chem. Soc., 68, 2350 (1946).When R¹ contains an amino group, the imidazole-4-carboxamide is obtainedfrom the appropriate N-substituted 2-(hydroxyimino)-3-oxobutanamidewhich is reduced to the corresponding 2-amino compound, eithercatalytically or chemically, depending on the amide involved. Theresulting 2-amino compound, is then reacted with potassium cyanate toproduce the imidazolecarboxamide.

The bromo compounds obtained above can be treated with hydrobromic acidin acetic acid to remove one or both of the N-acetyl groups. Theresulting imidazolone is then treated with the appropriate amine to givethe desired compounds of the present invention. If pyridine or anappropriate tertiary amine is used in the reaction, the process gives,directly, the quarternary ammonium compounds of the present invention.

Although the present process has been described using 1,3-unsubstitutedimidazolones, it is also possible to use the corresponding 1,3-diacetylcompounds or similarly substituted compounds but, when such compoundsare used, the amine will also react with the acyl group to give thedeacetylated imidazolone and an N-acyl amine. It is thus necessary touse an excess of the amine to allow for this reaction but this would notbe a desirable process when the amine used is not readily available andinexpensive.

The compounds in which R represents lower alkanoyl or benzoyl areobtained by reaction of the compounds in which R represents hydrogenwith an excess of the appropriate acid anhydride or acid chloride. Thecompounds wherein R¹ is hydroxy are obtained from the correspondingcompounds wherein R¹ is alkoxy by alkaline hydrolysis, with lithiumhydroxide in water being preferred for the process.

When the final product is obtained from any of the above reactions inthe form of an acid addition salt, it can be readily converted to thecorresponding free amine by standard procedures or, when the product isobtained as the free amine, it can be converted to the correspondingsalt by standard procedures.

The compounds of the present invention can be used in the treatment ofhypertension including primary or essential hypertension, hormonallyinduced hypertension, renal hypertension and chemically inducedhypertension. The compounds of the present invention can also be used asanti-thrombotics. They affect the coagulation of blood by preventing theaggregation of blood platelets, which play a dominant role in thromboticconditions both in the initial event and at the occlusive stage.Arterial thrombosis, particularly in arteries supplying the heart muscleand brain, is a leading cause of death and disability. In addition, thecompounds of the present invention in which --NR³ R⁴ contains apiperazine group can also be used in the treatment of cardiac failureincluding congestive heart failure, backward heart failure, forwardheart failure, left ventricular heat failure, or right ventricular heartfailure or in the treatment of any other condition which requires thestrengthening of heat action with a cardiotonic. In many respects, thesecompounds possess digitalis-like action.

Antihypertensive activity for the present compounds was demonstratedusing groups of 12 spontaneously hypertensive rats. Blood pressure wasmeasured by a pressure cuff occluder around the base of the tails of therats. The blood pressure was determined in the animals, test compoundwas administered orally in a vehicle at a dose of 50 mg/kg and bloodpressure was measured again at 1, 2, 3, 4 and 24 hours afteradministration of the test compound. The difference in blood pressureobserved was analyzed to establish if it was statistically significant.The vehicle used in administering the test compound did not have asignificant effect on blood pressure when used alone.

Cardiotonic activity for the present compounds was demonstrated by thefollowing procedure. A Walton-Brodie strain gage arch was surgicallyimplanted on the heart of anesthetized dogs to measure cardiaccontractile force. After the vital signs of the animal were stable for10 minutes, test compound was administered intravenously starting at adose of 0.3 mg/kg and continuing with higher doses of 1, 3 and 10 mg/kgif no effect is observed. Active compounds, such as compounds of thepresent invention, which increase cardiac contractile force measured inthis way exert a true positive inotropic effect, or a cardiotoniceffect.

Antithrombotic activity for the present compounds is demonstrated by thefollowing procedure. When adenosine diphosphate is added to citratedplatelet rich human plasma, a typical aggregation of blood plateletsoccurs. Antithrombotic activity is determined by adding a test compoundto the citrated platelet rich human plasma in concentrations of 3, 10,30 and 100 μg/ml and subsequently adding adenosine diphosphate andobserving the extent of inhibition of aggregation of blood platelets.

The compounds may be administered in various manners to achieve thedesired effect. The compounds may be administered alone or in the formof pharmaceutical preparations to the patient being treated eitherorally or parenterally, that is, intravenously or intramuscularly. Theamount of compound administered will vary with the severity of thehypertension, cardiac failure or blood clotting and the mode ofadministration. For oral administration the antihypertensively effectiveamount of compound is from about 0.1 mg/kg (milligrams per kilograms) ofpatient body weight per day to about 100 mg/kg of patient body weightper day and preferably from about 5 mg/kg of patient body weight per dayto about 30 mg/kg of patient body weight per day.

For parenteral administration the antihypertensively effective amount ofcompound is from about 0.01 mg/kg of patient body weight per day up toabout 50 mg/kg of patient body weight per day and preferably from about0.1 mg/kg of patient body weight per day up to about 20.0 mg/kg ofpatient body weight per day. For oral or parenteral administration thecardiotonically effective amount of compound is from about 0.1 mg/kg ofpatient body weight per day up to about 50 mg/kg of patient body weightper day and preferably from about 0.1 mg/kg of patient body weight perday up to about 20.0 mg/kg of patient body weight per day. For oral orparenteral administration the anticoagulant effective amount of compoundis from about 0.1 mg/kg of patient body weight per day up to about 100mg/kg of patient body weight per day and preferably from about 0.1 mg/kgof patient body weight per day up to about 50 mg/kg of patient bodyweight per day.

For oral administration a unit dosage may contain, for example, from 1to 100 mg of the active ingredient. For parenteral administration a unitdosage may contain, for example, from 0.5 to 50 mg of the activeingredient. Repetitive daily administration of the compounds may bedesired and will vary with the condition of the patient and the mode ofadministration.

As used herein the term patient is taken to mean a warm blooded animal,for example, birds, such as chickens and turkeys, and mammals, such asprimates, humans, sheep, horses, bovine cows and bulls, pigs, dogs,cats, rats and mice.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage forms can bea capsule which can be of the ordinary gelatin type containing, forexample, lubricants and inert filler, such as lactose, sucrose andcornstarch. In another embodiment the compounds of the invention can betableted with conventional tablet bases such as lactose, sucrose andcornstarch in combination with binders, such as acacia, cornstarch orgelatin, disintegrating agents such as potato starch or alginic acid,and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered asinjectable dosages of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water and oils with or without theaddition of a surfactant and other pharmaceutically acceptableadjuvants. Illustrative of oils which can be employed in thesepreparations are those of petroleum, animal, vegetable or syntheticorigin, for example, peanut oil, soybean oil and mineral oil. Ingeneral, water, saline, aqueous dextrose and related sugar solutions,ethanol and glycols such as propylene glycol or polyethylene glycol canbe used as liquid carriers for injectable solutions. Particularlypreferred are combinations of the above carriers such as aqueous ethanolor propylene glycol-aqueous ethanol at alkaline pH.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradeablepolymers or synthetic silicones, for example, Silastic, silicone rubbermanufactured by the Dow-Corning Corporation.

Following are illustrative pharmaceutical formulations which may beemployed in practicing the present invention:

    ______________________________________                                                                 Per Tablet                                           ______________________________________                                        Preparation of a Tablet Formulation                                           (a)  Ethyl 2,3-dihydro-5-[[4-(2-methoxy-                                                                     100    mg                                           phenyl)-1-piperazinyl]methyl]-2-oxo-                                          1H--imidazole-4-carboxylate hydrochloride                                (b)  Cornstarch                15     mg                                      (c)  Lactose                   33.5   mg                                      (d)  Magnesium stearate        1.5    mg                                      Preparation of a Parenteral Formulation                                       (a)  Ethyl 2,3-dihydro-5-[[4-(2-methoxy-                                                                     0.100  g                                            phenyl)-1-piperazinyl]methyl]-2-oxo-                                          1H--imidazole-4-carboxylate hydrochloride                                (b)  Sodium hydroxide          0.025  g                                       (c)  Ethanol                   1.516  g                                       (d)  Propylene glycol          8.264  g                                       (e)  Water for injection qs ad 20.0   ml                                      ______________________________________                                    

The following examples are set forth to illustrate the preparation ofcompounds employed in the present invention but should not be construedas limiting it in any way.

EXAMPLE 1

A solution of 15.8 g of N,N-dimethyl-2-(hydroxyimino)-3-oxobutanamide in400 ml of ethanol and 100 ml of 2 N hydrochloric acid is hydrogenatedover 2 g of 5% palladium on charcoal catalyst in a Parr shaker until onemolar equivalent of hydrogen is taken up (3-5 hours). The reactionmixture is then filtered to remove the catalyst and a solution of 16.2 gof potassium cyanate in 80 ml of water is added. The resulting solutionis refluxed for 1 hour and then concentrated until solid crystallizes.The solid is separated by filtration and recrystallized from 50% aqueousethanol to give2,3-dihydro-N,N,5-trimethyl-2-oxo-1H-imidazole-4-carboxamide meltingabove 300° C.

If the above procedures is repeated using the appropriate substituted2-(hydroxyimino)-3-oxobutanamide, the following compounds are obtained:

2,3-Dihydro-N,5-dimethyl-2-oxo-1H-imidazole-4-carboxamide melting above300° C.

2,3-Dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxamide melting above 300°C.

N-(tert-Butyl)-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxamide.

2,3-Dihydro-5-ethyl-N,N-dimethyl-2-oxo-1-H-imidazole-4-carboxamide.

EXAMPLE 2

To a stirred solution of 11.8 of2-(hydroxyimino)-N-(4-methoxyphenyl)-3-oxobutanamide in 30 ml of aceticacid and 10 ml of acetic anhydride at 20°-30° C. is added 10 g of zincdust and the mixture is stirred for 1 hour. Water (150 ml) is added, themixture is stirred for 2 hours, and the zinc is removed by filtration.The solvent is evaporated from the filtrate under reduced pressure andthe resulting residue is recrystallized from methanol to give2-acetylamino-N-(4-methoxyphenyl)-3-oxobutanamide.

The product obtained in the preceding paragraph (10.6 g) is dissolved in20 ml of 6 N hydrochloric acid and the solution is allowed to stand atroom temperature for 5 minutes. A solution of 9.7 g of potassium cyanatein 80 ml of water is added and the mixture is stirred at roomtemperature for 16 hours. The precipitate which forms is separated byfiltration and recrystallized twice from 50% aqueous ethanol to give2,3-dihydro-N-(4-methoxyphenyl)-5-methyl-2-oxo-1H-imidazole-4-carboxamidemelting at about 299°-301° C. (dec.).

If the above procedure is repeated using the appropriate N-substituted2-(hydroxyimino)-3-oxobutanamide, the following compounds are obtained:

2,3-Dihydro-5-methyl-2-oxo-N-phenyl-1H-imidazole-4-carboxamide.

2,3-Dihydro-5-methyl-N-(2,4-dimethylphenyl)-2-oxo-1H-imidazole-4-carboxamide.

2,3-Dihydro-5-ethyl-2-oxo-N-phenyl-1H-imidazole-4-carboxamide.

EXAMPLE 3

A mixture of 54.5 g of ethyl2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate and 240 ml ofacetic anhydride is refluxed for 13 hours. The mixture is distilled toremove 150 ml of acetic anhydride and acetic acid; this is replaced byfresh acetic anhydride and refluxing is resumed. After a total of 22hours of reflux, excess acetic anhydride is evaporated under reducedpressure and the resulting residue is triturated with cyclohexane andthen recrystallized from cyclohexane to give ethyl1,3-diacetyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylatemelting at about 56°-58° C.

If the above procedure is repeated using acetic anhydride and theappropriate substituted 2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acidderivative, the following compounds are obtained:

1,3-Diacetyl-2,3-dihydro-N,N,5-trimethyl-2-oxo-1H-imidazole-4-carboxamide.

1,3-Diacetyl-2,3-dihydro-N,5-dimethyl-2-oxo-1H-imidazole-4-carboxamide.

1,3-Diacetyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxamide.

1,3-Diacetyl-N-(tert-butyl)-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxamide.

1,3-Diacetyl-2,3-dihydro-5-ethyl-N,N-dimethyl-2-oxo-1H-imidazole-4-carboxamide.

1,3-Diacetyl-2,3-dihydro-N-(4-methoxyphenyl)-5-methyl-2-oxo-1H-imidazole-4-carboxamide.

1,3-Diacetyl-2,3-dihydro-5-methyl-2-oxo-N-phenyl-1H-imidazole-4-carboxamide

1,3-Diacetyl-2,3-dihydro-5-methyl-N-(2,4-dimethylphenyl)-2-oxo-1H-imidazole-4-carboxamide.

1,3-Diacetyl-2,3-dihydro-5-ethyl-2-oxo-N-phenyl-1H-imidazole-4-carboxamide.

EXAMPLE 4

A mixture of 12.7 g (0.050 mole) of ethyl1,3-diacetyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate, 9.3g (0.052 mole) of N-bromosuccinimide and about 100 mg of benzoylperoxide in 400 ml of carbon tetrachloride is stirred at refluxtemperature for 4 hours. The mixture is then cooled and filtered toremove the succinimide which formed. The solvent is evaporated from thefiltrate to give5-(bromomethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylateas an oil.

If the above procedure is repeated using N-bromosuccinimide and theappropriate substituted1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acidderivative, the following compounds are obtained:

5-(Bromomethyl)-1,3-diacetyl-2,3-dihydro-N,N-dimethyl-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-1,3-diacetyl-2,3-dihydro-N-methyl-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-N-(tert-butyl)-1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxamide.

5-(1-Bromomethyl)-2,3-dihydro-1,3-diacetyl-N,N-dimethyl-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-1,3-diacetyl-2,3-dihydro-N-(4-methoxyphenyl)-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-N-phenyl-1H-imidazole-4carboxamide.

5-(Bromomethyl)-1,3-diacetyl-2,3-dihydro-N-(2,4-dimethylphenyl)-2-oxo-1H-imidazole-4-carboxamide.

5-(1-Bromoethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-N-phenyl-1H-imidazole-4-carboxamide.

Ethyl5-(bromomethyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-imidazole-4-carboxylate.

EXAMPLE 5

Crude ethyl5-(bromomethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylateis dissolved in 30% hydrobromic acid in acetic acid and the solution isallowed to stand at room temperature for 4 hours. The solid whichprecipitates is separated by filtration and dried in vacuo at 80° C.over potassium hydroxide to give ethyl3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylatemelting at about 193°-194° C. (dec.).

If the above procedure is repeated using the appropriate substituted1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acidderivative, the following compounds are obtained:

5-(Bromomethyl)-2,3-dihydro-N,N-dimethyl-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-2,3-dihydro-N-methyl-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-N-(tert-butyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxamide.

5-(1-Bromoethyl)-2,3-dihydro-N,N-dimethyl-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-2,3-dihydro-N-(4-methoxyphenyl)-2-oxo-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-2,3-dihydro-2-oxo-N-phenyl-1H-imidazole-4-carboxamide.

5-(Bromomethyl)-2,3-dihydro-N-(2,4-dimethylphenyl)-2-oxo-1H-imidazole-4-carboxamide.

5-(1-Bromoethyl)-2,3-dihydro-2-oxo-N-phenyl-1H-imidazole-4-carboxamide.

EXAMPLE 6

To a cooled solution (0° C.) of 2 g of 1-(2-methoxyphenyl)piperazine and2.1 g of triethylamine in 40 ml of ethanol is added 2.9 g of ethyl3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate.The resulting solution is stirred at 0° C. for 4 hours, 30 ml ofice-water is added and the mixture is filtered. One equivalent ofhydrochloric acid is added to the filtrate and it is evaporated todryness. The residue crystallizes from a mixture of ethanol and ethylacetate (1:1) and is recrystallized from that solvent mixture to giveethyl2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylatehydrochloride melting at about 227° C. (dec.). The free base of thiscompound has the following structural formula: ##STR6##

EXAMPLE 7

If 1-(2-methoxyphenyl)piperazine is reacted with5-(bromomethyl)-2,3-dihydro-N,N-dimethyl-2-oxo-1H-imidazole-4-carboxamideand similar compounds according to the procedure of Example 6, thefollowing compounds are obtained:

2,3-Dihydro-N,N-dimethyl-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxamidehydrochloride.

2,3-Dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-N-methyl-2-oxo-1H-imidazole-4-carboxamidehydrochloride.

2,3-Dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxamidehydrochloride.

N-(tert-butyl)-2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxamidehydrochloride.

2,3-Dihydro-N,N-dimethyl-5-[1-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]2-oxo-1H-imidazole-4-carboxamidehydrochloride.

2,3-Dihydro-N-(4-methoxyphenyl)-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxamidehydrochloride.

2,3-Dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-N-phenyl-2-oxo-1H-imidazole-4-carboxamidehydrochloride.

2,3-Dihydro-N-(2,4-dimethylphenyl)-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxamidehydrochloride.

2,3-Dihydro-5-[1-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-phenyl-2-oxo-1H-imidazole-4-carboxamidehydrochloride.

Ethyl2,3-dihydro-1,3-dimethyl-5-[[4-(2-methoxphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylatehydrochloride.

EXAMPLE 8

If the procedure of Example 6 is repeated using ethyl3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylateand the appropriate secondary amine, the following compounds areobtained:

Ethyl5-[(dimethylamino)methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylatehydrochloride.

Ethyl5-[(diethylamino)methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylatehydrochloride.

Ethyl2,3-dihydro-2-oxo-5-[(1-pyrrolidinyl)methyl]-1H-imidazole-4-carboxylatehydrochloride.

Ethyl 2,3-dihydro-2-oxo-5-[(1-piperidinyl)]-1H-imidazole-4-carboxylatehydrochloride.

Ethyl2,3-dihydro-5-[(4-morpholinyl)methyl]-2-oxo-1H-imidazole-4-carboxylatehydrochloride.

Ethyl2,3-dihydro-5-[(4-methyl-piperazinyl)methyl]-2-oxo-1H-imidazole-4-carboxylatehydrochloride.

Ethyl5-[[4-(4-chlorophenyl)-1-piperazinyl]methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylatehydrochloride.

Ethyl2,3-dihydro-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-oxo-1H-imidazole-4-carboxylatehydrochloride.

Ethyl2,3-dihydro-5-[[4-(3-trifluoromethylphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylatehydrochloride.

EXAMPLE 9

The ethyl2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylateobtained in Example 6 is dissolved in a solution of 3 equivalents oflithium hydroxide in water. The solution is allowed to stand at roomtemperature for 48 hours before it is neutralized carefully with 2equivalents of hydrochloric acid. The precipitate which forms isseparated by filtration and recrystallized from a mixture of ethanol andethyl acetate to give2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylicacid.

EXAMPLE 10

To a solution of 10.4 g of crude ethyl5-(bromomethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylatein 100 ml of dry tetrahydrofuran, cooled in an ice bath under argon,there is added gaseous trimethylamine for 7 minutes. The mixture isstirred at 0° C. for 15 minutes and then evaporated to dryness. To theresidue is added 50 ml of 31% hydrogen bromide in acetic acid and themixture is warmed briefly on a steam bath to about 50° C. to bring aboutdissolution. It is then allowed to stand at room temperature for 1 hourbefore it is evaporated to dryness. Water (50 ml) is added to theresidue and the resultant aqueous mixture is washed with methylenechloride, treated with charcoal, filtered through diatomaceous earth,and evaporated to dryness. The resultant residue is crystallized from amixture of ethanol and ethyl acetate (1:3) and then recrystallized fromethanol to give5-(ethoxycarbonyl)-2,3-dihydro-N,N,N-trimethyl-2-oxo-1H-imidazole-4-methanaminiumbromide monohydrate melting at about 199°-200° C. (dec.). This compoundhas the following structural formula: ##STR7##

EXAMPLE 11

The sodium salt of ethyl2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate is prepared from4.9 g of ethyl 2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate in100 ml of methanol with the addition of 1.6 g of sodium methoxide. Amixture is prepared from 8.0 g of this sodium salt, 120 ml ofdimethylsulfoxide and 19.5 g of methyl iodide. This mixture is stirredat room temperature for 60 minutes and then poured into 800 ml of water.The resulting mixture is then extracted with methylene chloride and thesolvent is evaporated from the extract to give ethyl 2,3;l-dihydro-1,3,5-trimethyl-2-oxo-1H-imidazole-4-carboxylate.

What is claimed is:
 1. A compound of the formula: ##STR8## wherein R ishydrogen, lower alkyl of 1-4 C, lower alkanoyl of 2-4 C, or benzoyl; R¹is hydroxy, lower alkoxy of 1-4 C, amino, (lower alkyl)amino, (loweralkyl)₂ amino or --NHR₅ wherein R₅ is phenyl, methylphenyl,dimethylphenyl or methoxyphenyl; R² is hydrogen or lower alkyl of 1-4 C;and --NR³ R⁴ is ##STR9## wherein R⁶ is lower alkyl of 1-4 C, phenyl,halophenyl, methylphenyl, methoxyphenyl or trifluoromethylphenyl; andthe pharmaceutically acceptable acid addition salts and the lower alkylquaternary ammonium salts of the aforesaid compounds.
 2. A compoundaccording to claim 1 which has the formula: ##STR10## wherein R¹ ishydroxy, lower alkoxy of 1-4 C, amino, (lower alkyl)amino, (loweralkyl)₂ amino or --NHR₅ wherein R₅ is phenyl, methylphenyl,dimethylphenyl or methoxyphenyl; and --NR³ R⁴ is ##STR11## wherein R⁶ islower alkyl of 1-4 C, phenyl, halophenyl, methylphenyl, methoxyphenyl ortrifluoromethylphenyl.
 3. A compound according to claim 1 which has theformula: ##STR12## wherein R¹ is lower alkoxy of 1-4 C, --NR³ R⁴ is##STR13## wherein R⁶ is lower alkyl of 1-4 C, phenyl, halophenyl,methylphenyl, methoxyphenyl or trifluoromethylphenyl.
 4. A compoundaccording to claim 1 which has the formula: ##STR14## wherein R⁶ islower alkyl of 1-4 C, phenyl, halophenyl, methylphenyl, methoxyphenyl ortrifluoromethylphenyl.
 5. A compound according to claim 1 which is ethyl2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylate.